title: A phase I trial of imetelstat in children with refractory or recurrent solid tumors: a Children's Oncology Group Phase I Consortium Study (ADVL1112).
abstract: OBJECTIVE
  Imetelstat is a covalently-lipidated 13-mer thiophosphoramidate oligonucleotide that acts as a potent specific inhibitor of telomerase. It binds with high affinity to the template region of the RNA component of human telomerase (hTERC) and is a competitive inhibitor of telomerase enzymatic activity. The purpose of this study was to determine the recommended phase II dose of imetelstat in children with recurrent or refractory solid tumors.
  
  
  METHODS
  Imetelstat was administered intravenously more than two hours on days 1 and 8, every 21 days. Dose levels of 225, 285, and 360 mg/m(2) were evaluated, using the rolling-six design. Imetelstat pharmacokinetic and correlative biology studies were also performed during the first cycle.
  
  
  RESULTS
  Twenty subjects were enrolled (median age, 14 years; range, 3-21). Seventeen were evaluable for toxicity. The most common toxicities were neutropenia, thrombocytopenia, and lymphopenia, with dose-limiting myelosuppression in 2 of 6 patients at 360 mg/m(2). Pharmacokinetics is dose dependent with a lower clearance at the highest dose level. Telomerase inhibition was observed in peripheral blood mononuclear cells at 285 and 360 mg/m(2). Two confirmed partial responses, osteosarcoma (n = 1) and Ewing sarcoma (n = 1), were observed.
  
  
  CONCLUSIONS
  The recommended phase II dose of imetelstat given on days 1 and 8 of a 21-day cycle is 285 mg/m(2).
authors.affiliation: Authors' Affiliations: Texas Children's Cancer Center and Department of Pediatrics; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas; Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Children's Oncology Group, Arcadia; Geron Corporation, Menlo Park, California; Department of Oncology, Mayo Clinic, Rochester; and Department of Pediatrics, Hematology-Oncology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Thompson
authors.forename: Rachid
authors.initials: R
authors.lastname: Drissi
authors.forename: Jodi A
authors.initials: JA
authors.lastname: Muscal
authors.forename: Eshini
authors.initials: E
authors.lastname: Panditharatna
authors.forename: Maryam
authors.initials: M
authors.lastname: Fouladi
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Ingle
authors.forename: Charlotte H
authors.initials: CH
authors.lastname: Ahern
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Tong
authors.initials: T
authors.lastname: Lin
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Weigel
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D001859:Bone Neoplasms / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009447:Neuroblastoma / Q000188:drug therapy*; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D009841:Oligonucleotides; D012512:Sarcoma, Ewing / Q000188:drug therapy*; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D009841:Oligonucleotides; D009536:Niacinamide; D019098:Telomerase; C519562:imetelstat